Endocannabinoids (eCBs) and their receptors are found throughout the human body: nervous system, internal organs, connective tissues, glands, and immune cells. The eCB system has a homeostatic role, having been characterized as “eat, sleep, relax, forget, and protect.”
It is known that eCBs have a role in the pathology of many disorders while also serving a protective function in certain medical conditions.
It has been proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent clinical eCB deficiency syndromes (CEDS). Deficiencies in eCB signaling could be also involved in the pathogenesis of depression. In human studies, eCB system deficiencies have been implicated in schizophrenia, multiple sclerosis (MS), Huntington’s disease, Parkinson’s disease, anorexia, chronic motion sickness, and failure to thrive in infants.
The eCB system represents a microcosm of psycho-neuroimmunology or “mind–body” medicine. The eCB system consists of receptors, endogenous ligands, and ligand metabolic enzymes. A variety of physiological processes occur when cannabinoid receptors are stimulated.
Cannabinoid receptor type 1 (CB1) is the most abundant G-protein–coupled receptor. It is expressed in the central nervous system, with particularly dense expression in (ranked in order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala. CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, connective and musculoskeletal tissues, and the gonads. CB2 is principally associated with cells governing immune function, although it may also be expressed in the central nervous system.The most well-known eCB ligands are N-arachidonyl-ethanolamide (anandamide or AEA) and sn-2-arachidonoyl-glycerol (2-AG).
AEA and 2-AG are released upon demand from cell membrane phospholipid precursors. This “classic” eCB system has expanded with the discovery of secondary receptors, ligands, and ligand metabolic enzymes. For example, AEA, 2-AG, N-arachidonoyl glycine (NAGly), and the phytocannabinoids Δ9-THC and CBD may also serve, to different extents, as ligands at GPR55, GPR18, GPR119, and several transient receptor potential ion channels (e.g., TRPV1, TRPV2, TRPA1, TRPM8) that have actions similar to capsaicin.
The effects of AEA and 2-AG can be enhanced by “entourage compounds” that inhibit their hydrolysis via substrate competition, and thereby prolong their action through synergy and augmentation. Entourage compounds include N-palmitylethanolamide (PEA), N-oleoylethanolamide (SEA), and cis-9-octadecenoamide (OEA or oleamide) and may represent a novel route for molecular regulation of endogenous cannabinoid activity.
Additional noncannabinoid targets are also linked to cannabis. G-protein–coupled receptors provide noncompetitive inhibition at mu and delta opioid receptors as well as norepinephrine, dopamine, and serotonin. Ligand-gated ion channels create allosteric antagonism at serotonin and nicotinic receptors, and enhance activation of glycine receptors. Inhibition of calcium, potassium, and sodium channels by noncompetitive antagonism occurs at nonspecific ion channels and activation of PPARα and PPARγ at the peroxisome proliferator-activated receptors is influenced by AEA.
THC is known to be the major psychoactive component of cannabis mediated by activation of the CB1 receptors in the central nervous system; however, this very mechanism limits its use due to untoward adverse effects. It is now accepted that other phytocannabinoids with weak or no psychoactivity have promise as therapeutic agents in humans. The cannabinoid that has sparked the most interest as a nonpsychoactive component is CBD.
Unlike THC, CBD elicits its pharmacological effects without exerting any significant intrinsic activity on CB1 and CB2 receptors. Several activities give CBD a high potential for therapeutic use, including antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective effects. CBD in combination with THC has received regulatory approvals in several European countries and is under study in registered trials with the FDA. And, some states have passed legislation to allow for the use of majority CBD preparations of cannabis for certain pathological conditions, despite lack of standardization of CBD content and optimal route of administration for effect.
Specific applications of CBD have recently emerged in pain (chronic and neuropathic), diabetes, cancer, and neurodegenerative diseases, such as Huntington’s disease. Animal studies indicate that a high dose of CBD inhibits the effects of lower doses of THC. Moreover, clinical studies suggest that oral or oromucosal CBD may prolong and/or intensify the effects of THC. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg per day) may exert a therapeutic effect for epilepsy, insomnia, and social anxiety disorder. Nonetheless, such doses of CBD have also been shown to cause sedation.